1. Field of the Invention
The present invention generally relates to novel opioid receptor-active compounds and their pharmaceutically acceptable salts, to methods of preparing the compounds, to pharmaceutical compositions containing the compounds, and to their use as opioid receptor-active agents. These compounds and compositions have utility in a variety of therapeutic areas, including use as nonaddictive analgesics and in a treatment for opiate addiction.
2. Brief Description of Related Technology
Opiates are well known for their usefulness in the treatment of a variety of maladies. Opiates, such as morphine, are potent analgesics, but their usefulness is limited because of adverse side effects, such as physical addictiveness and withdrawal properties. Morphine and related opiates also exhibit other adverse side effects, such as respiratory depression, mood changes, and decreased intestinal motility with concomitant constipation, nausea, vomiting, and alterations in the endocrine and autonomic nervous systems.
Opiates exert their effects by interacting with high-affinity opioid receptors. The opioid receptor was one of the first human receptors hypothesized, and, later, demonstrated to exist in mammalian brain. Three types of opioid receptors have been proposed, and are now widely referred to as the .mu., .delta. and .kappa. types. Subtypes of each type of opioid receptor also have been proposed.
Considerable research has been directed to the opioid receptors, for example, to determine their distinct pharmacological profiles, anatomical distributions, and functions. In particular, it is known that opioid receptors are G-protein coupled receptors, and that they are widely distributed in mammalian systems, both in the central nervous system and in the periphery. See, for example, J. V. Aldrich in Burger's Medicinal Chemistry and Drug Discovery, Vol. 3, M. E. Wolff, Ed., John Wiley, Fifth Ed., p. 321-439 (1996).
The .delta. opioid receptors are abundant in the central nervous system and play a role in spinal analgesia, gastrointestinal motility, and various hormonal functions. See, for example, R. Spanagel et al., J. Neurochem., 55, p. 1743-50 (1990). Cells of the immune system also have been shown to have .delta. opioid receptors on their surface. See, for example, D. J. J. Carr et al., Cell Immunol., 116, p. 44-51 (1988). Thus, immune response is stimulated by .delta. opioid receptor agonists (see, for example, S. Mazumder et al., Immunol. Lett., 35, p. 33-38 (1993)), and suppressed by .delta. opioid receptor antagonists (see, for example, K. Arakawa et al., Transplantation, 53, p. 951-53 (1992)).
The .mu. opioid receptors bind morphine-like drugs and mediate opiate phenomena associated with morphine, including analgesia, euphoria, cardiovascular and respiratory functions, and physical dependence. See, for example, K. A. Sporer, Ann. Int. Med., 130, p. 584-90 (1999), and D. J. Nutt, The Lancet, 347, p. 31-36 (1996).
The .kappa. opioid receptors are widely distributed in the central and peripheral nervous systems, and mediate a spectrum of functions including the modulation of drinking, water balance, food intake, gut motility, temperature control, and various endocrine functions.
The following structure is the morphinone structure that has demonstrated opioid receptor activity. The numbers 6, 7, and 17 designate various important ring positions of the morphinone structure. Oxymorphone, a ##STR2##
morphinone wherein R is methyl, is a nonselective agonist for the .mu., .delta. and .kappa. opioid receptors, and has been used to design a series of fused heterocyclic derivatives at the 6,7 positions. Naltrexone, a morphinone wherein R is cyclopropylmethyl, is a nonselective antagonist of moderate to high affinity for the .mu., .delta. and .kappa. opioid receptors, and also has served as a template for derivatization at the 6,7-positions.
Compounds that act as .kappa. opioid receptor antagonists have been discovered only recently. A peptide derivative of dynorphin A-(1-11) recently has been reported to be a .kappa. opioid receptor antagonist. See Q. Wan et al., J. Med. Chem., 42, p. 3011 (1999). The compound norBNI is a nonpeptide .kappa. opioid receptor antagonist of moderate selectivity. See P. S. Portoghese et al., Life Sci., 40, p. 1287-92 (1987). A nonselective .kappa. opioid receptor antagonist is [(-)-(1R,5R,9R)-(5,9-diethyl-2-(3-furylmethyl)-2'-hydroxy-6,7-benzomorphan ], reported by J. V. Aldrich in Burger's Medicinal Chemistry and Drug Discovery, Vol. 3, M. E. Wolff Ed., John Wiley, Fifth Ed., p. 321-439 (1996).
Because .kappa. opioid receptor antagonists have been investigated only recently, insufficient information exists with respect to structure-activity relationships of .kappa. opioid receptor antagonists. However, it is known that the 17-N-methyl morphinan derivatives are agonists, while the 17-N-cyclopropylmethyl morphinan derivatives are antagonists.
The pharmacological effects of .kappa. opioid receptor agonists and antagonists only now are being investigated. It is known that .kappa. opioid receptors, when stimulated, can produce analgesia. See, for example, R. Spanagel et al., J. Neurochem., 55, p. 1743-50 (1990). However, it has recently been reported that one .kappa. opioid receptor agonist increased pain when used as a postoperative analgesic. See H. Machelska et al., J. Pharmcol. Exptl. Therap., 290, p. 354-61 (1999). Kappa opioid receptor agonists also have been shown to reduce blood pressure in rats. See M. M. McConnaughey et al., J. Pharm. Pharmacol., 50, p. 1121-25 (1998). One .kappa. opioid receptor antagonist has been shown to reduce significantly the self-administration of cocaine in mice, therefore suggesting involvement of the endogenous .kappa. opioid receptor system in the mechanisms of self-administration of cocaine. See A. V. Kuzmin et al., Eur. J. Pharmacol., 358, p. 197-202 (1998).
Accordingly, a continuing need exists for compounds and combinations of compounds that act as agonists or antagonists at the .mu., .delta. and .kappa. type opioid receptors, or at the subtypes of these receptors. It also would be desirable to provide compounds or a combination of compounds that exhibit potent analgesic effects without demonstrating the addictive and withdrawal properties associated with present nonpeptide opioid analgesics.